Reaction Calorimeters

A reaction calorimeter is a tool used by scientists in chemical and pharmaceutical development to measure the amount of energy released or absorbed by a chemical or physical reaction.

It typically consists of a stirred tank reactor of variable size in which the temperature of the reaction mass is monitored and controlled accurately together with all relevant critical process parameters.

Reaction Calorimeters allow the investigation of chemical processes under process-like conditions, providing a full set of information about the scalability and safety of the process.

Depending on the stage of development, various additional information might be relevant and thus, complementary data (e.g. analytical data from IR, HPLC or the like may be collected and integrated with the heat flow data).

Reaction calorimetry measures the heat released from a chemical reaction or physical process and provides the fundamentals of the thermochemistry and kinetics of a reaction.

The information obtained is essential to describe the heat release of a chemical reaction over time, and to safely transfer it from lab to plant.

Reaction calorimetry uncovers unexpected behavior and makes any scalability issues visible and quantifiable. It also helps to identify issues related to heat and mass transfer or mixing, and allows the determination of the correct temperature, stirring or dosing profile of a given reaction or process. The information obtained is subsequently used to evaluate the risk, scalability and criticality of a process.

Reaction calorimetry data are used to characterize, optimize and understand process parameters in a controlled, accurate and reproducible environment, and to enable safe scale-up and transfer into manufacturing.

Heat flow calorimetry is the most simple and robust method to determine the heat released by a chemical reaction or physical process, and is supported by all METTLER TOLEDO reaction calorimetry workstations. Heat flow calorimetry is applicable under most conditions, highly sensitive and offers excellent repeatability.

The heat flow calorimetry principle is based on the measurement of the temperature difference across the reactor wall, which is then converted into a heat flow by means of the calibration factor.

The calibration factor depends on the thermal conductivity and thickness of the reactor wall, the thermal resistance of the reaction mass film, the thermal resistance of the oil film and the heat exchange area, and is determined by means of an electrical heater.

The method of heat flow calorimetry is applicable in both small and large scale, and is the basis for for all chemical process development projects, process scale-up and chemical process safety investigations.

EasyMax 102 HFCal,EasyMax 402 HFCal and Optimax HFCal are small-scale heat flow calorimeters that combine the benefits of a synthesis workstation and a reaction calorimeter. These small-scale reaction calorimeters are designed for process safety screening and scale-up, and provide relevant reaction information early in the development process.

The RC1mx reaction calorimeter is the industry “Gold Standard” for measuring heat profiles, chemical conversion and heat transfer under process-like conditions. The RC1mx provides a modern solution with a high-performance thermostat as the centerpiece. RC1mx allows chemical and safety engineers to optimize processes under safe conditions, while determining all critical process parameters and reducing the risk of failure on a large scale.

Reaction calorimeters allow the efficient and safe development of processes at scale.

As a reaction is scaled from lab to plant, scalability problems may suddenly emerge for various reasons. In the worst case, unidentified reaction risks may lead to a runaway reaction followed by an explosion. The causes of thermal incidents are often attributed to:

• Lack of understanding of the chemistry or the thermochemistry of a process
• Inability to remove heat
• Bad or poorly understood mixing behavior
• Human factors

Incidents can be avoided by determining the relevant data at lab scale. The lab work is performed under process-like conditions using reaction calorimeters, so that the results can be directly applied to larger-scale operations.

Reaction calorimetry provides a high level of process understanding, so that the necessary procedures can be performed routinely, robustly and to the required quality standards.

Accurate and precise heat flow data is essential for transitioning from lab to plant. A high-performance heating and cooling system combined with a sensitive temperature measurement and control system are pre-requisites to obtain accurate and precise heat information of a chemical process. This includes details about the heat of reaction, the total heat flow balance, the mass and heat transfer and the specific heat of the reaction mass.

The total heat flow balance of a chemical process itself includes a variety of thermal effects, such as accumulation of heat, heat exchange due to reactant or solvent additions, heat due to changing viscosity, heat loss, etc.

For reactions that are run under changing temperature conditions, heat accumulation becomes an important factor in the calculation of the heat of reaction (heat released as a function of time).

METTLER TOLEDO reaction calorimeters and iControl software suite use sophisticated calculation algorithms. These take into account the dynamic behavior of the reactor wall, the heat capacities of the vessel and the reactor inserts – providing calorimetric data of maximum accuracy and precision.

The development and optimization of chemical processes requires the determination of a variety of different types of information in order to make correct decisions. It is common to collect analytical data, such as IR, Raman, particle size distribution or concentration online and in real time. Collecting heat release data online and in real time is undoubtedly a great advantage when investigating chemical processes.

Reactor systems that enable the scanning of reactions for heat release in real time provide instantaneous feedback of the progress of the reaction and allow users to immediately take corrective actions. Online heat data in real time are often used to control the process by adjusting critical process parameters, such as the addition rate of reactants, controlling the pressure, the stirring speed or any other process parameter.

With the RTCal reactor, the researcher uses a PAT (Process Analytical Technology) tool that allows tracking reactions online and in real time. It delivers valuable heat information about the progress of the reaction without the need of expert knowledge. RTCal technology uses heat flux sensors that are built into the reactor, detecting the heat flow across the wall of the reactor.

The measurement of heat data with RTCal is independent of the properties or the behavior of the reaction mass. Hence, no calibration procedures need to be run before, during or after the reaction, which reduces the experiment time substantially.

Whenever a new or modified process needs to be taken from lab to plant, the different aspects that may be critical or affect the performance or outcome of the process need to be investigated. In a few cases, the route chosen is also not scalable because of expensive or scarce starting materials, conditions that are difficult to control in large vessels or potential safety hazards and thus, needs to be modified. This requires investigation of scale-dependent variables, such as dosing rates, mixing or mass transfer. However, one of the key pieces of information to move a process into manufacturing safely is the understanding of the total heat released, the heat release rate, the accumulation of reactant(s) or energy as well as the stability of the reaction mass and the individual components.

Reaction calorimetry studies provide evidence of the critical process parameters and their impact on the process, the manufacturability, the yield and quality of the product or intermediate.

Since chemical reactions are influenced by several parameters such as concentration, addition rate, temperature, solvent, catalyst and pH value, the seamless integration of online analytics or automated sampling tools into the reaction calorimeter increases the value of the study tremendously.

Data-rich experiments comprising of both calorimetry and analytical information effectively support today's needs for developing safe and robust processes fast and transferring them from lab to plant effectively.

Bringing new chemical or pharmaceutical entities to market successfully requires innovative ideas, creative researchers and modern tools that support an effective development workflow.

Experiments are to be carried out at small scale due to lack of material, while the data obtained needs to be precise. It is imperative that data is applied to statistical approaches (e.g. Design of Experiments (DoE) Studies), but also experiments based on traditional procedures are trustworthy, allowing for the identification of scalability and potential safety issues at an early stage in development. This enables increased productivity in chemical development and also ensures that a process can be carried out safely and economically at large scale.

Chemical and pharmaceutical industries often use complex chemical processes in which large amounts of energy can be released. Knowing and understanding the potential risks is critical, and a prerequisite for safe manufacturing of chemical and pharmaceutical products.  This includes the understanding of the thermodynamics of the desired reaction, as well as that of a possible undesired reaction.

The RC1mx reaction calorimeter provides reliable data to calculate the relevant safety parameters of the main reaction with the highest degree of confidence. iC Safety turns experimental data into safety information, combines it with data from the undesired reaction and presents the thermal risk (e.g. thermal accumulation, ΔTadiabatic, MTSR) in a concise and easy-to-understand format (e.g. table, runaway and criticality graph). 

Chemical process safety and related-applications using reaction calorimeters are referenced in many publications, including:

• Hua, M., Qi, M., Pan, X., Yu, W., Zhang, L., & Jiang, J. (2017). Inherently safer design for synthesis of 3-methylpyridine-N-oxide. Process Safety Progress, 37(3), 355–361. https://doi.org/10.1002/prs.11952
• Jyotsna, G. K., Srikanth, S., Ratnaparkhi, V., Rakeshwar, B. (2017). Reaction calorimetry as a tool for thermal risk assessment and improvement of safe scalable chemical processes. Inorg Chem Ind J.,12(1),110.
• Lakshminarasimhan, T. (2014). Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low Temperature Reactions by Kinetic Fitting of Nonisothermal Heat Data from Reaction Calorimeter (RC1e). Organic Process Research & Development, 18(2), 315–320. https://doi.org/10.1021/op400301f
• Mitchell, C. W., Strawser, J. D., Gottlieb, A., Millonig, M. H., Hicks, F. A., & Papageorgiou, C. D. (2014). Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions. Organic Process Research & Development, 18(12), 1828–1835. https://doi.org/10.1021/op500207r
• Monteiro, A. M., & Flanagan, R. C. (2017). Process Safety Considerations for the Use of 1 M Borane Tetrahydrofuran Complex Under General Purpose Plant Conditions. Organic Process Research & Development, 21(2), 241–246. https://doi.org/10.1021/acs.oprd.6b00407
• Pečar, D., & Goršek, A. (2015). Saponification reaction system: a detailed mass transfer coefficient determination. Acta Chimica Slovenica, 62(1). https://doi.org/10.17344/acsi.2014.1110
• Wang, J., Huang, Y., Wilhite, B. A., Papadaki, M., & Mannan, M. S. (2018). Toward the Identification of Intensified Reaction Conditions Using Response Surface Methodology: A Case Study on 3-Methylpyridine N-Oxide Synthesis. Industrial & Engineering Chemistry Research, 58(15), 6093–6104. https://doi.org/10.1021/acs.iecr.8b03773
• Yang, Q., Canturk, B., Gray, K., McCusker, E., Sheng, M., & Li, F. (2018). Evaluation of Potential Safety Hazards Associated with the Suzuki–Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species. Organic Process Research & Development, 22(3), 351–359. https://doi.org/10.1021/acs.oprd.8b00001